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Recurrent implantation failure: British fertility society Guidelines2020

Prof Aboubakr Mohamed Elnashar

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Recurrent implantation failure: British fertility society Guidelines2020

  1. 1. 8/19/2020 1 MANAGEMENT OF RECURRENT IMPLANTATION FAILURE British Fertility Society Guidelines, 2020 Prof. Aboubakr Elnashar Benha university , EgyptABOUBAKR ELNASHAR 8/19/2020 2 IMPLANTATION  The classical model of implantation where the embryo undergoes rolling, apposition, adhesion& invasion into the endometrium (Genbacev et al., 2003) is being challenged by  New evidence suggesting mutual attraction between the embryo & decidualised endometrial stromal cells (Teklenburg et al., 2010).  An active interplay between the embryo& receptive endometrium ABOUBAKR ELNASHAR
  2. 2. 8/19/2020 3 Apposition Adhesion InvasionEmbryo Endometrial stroma Invading trophoblast Uterine epithelium  Starts 5 to 7 days after fertilization of the oocyte: formation of a gestation sac (Hochschild et al., 2017).  Continue up to 22 w gestation ABOUBAKR ELNASHAR 8/19/2020 4  Implantation rates/ET: 20-30% (Voullaire et al., 2002).  Cumulative LBR: after  3 cycles of IVF: 42-57%  6 cycles: 44-75% (IVF cycles in UK between 1999 and 2017; McLernon et al., 2016). ABOUBAKR ELNASHAR
  3. 3. 8/19/2020 5 RIF  Definition:  Failure to conceive after repeated attempts of IVF (Coughlan et al., 2014).  The number of failed treatments has not been universally agreed.  Distinct from Recurrent failure of ART due to  Patient characteristics or  Treatment protocol failure  ±include scenarios where no embryos are transferred (Ferraretti et al., 2011). ABOUBAKR ELNASHAR 8/19/2020 6  After 3 consecutive ET of  at least 4 good-quality embryos  in a woman under the age of 40 ys (Simon and Laufer, 2012; Coughlan et al, 2013).  After 2 consecutive ET (fresh or frozen) of  at least 4 good-quality clevage stage embryos or  2 good quality blastocysts (Polanski et al, 2014)  Absence of a positive pregnancy test after 3 consecutive ET of good quality embryos (BFS,2020) ABOUBAKR ELNASHAR
  4. 4. 8/19/2020 7 Incidence  10% of the cycles (Margalioth et al, 2006). Impact  Distress to couples  Frustration to doctor  Increases the cost of the procedure  Management  Major challenge to clinicians & embryologists. ABOUBAKR ELNASHAR 8/19/2020 8  Causes: I. Endometrial factors I. Gamete/Embryo: ± of male or female origin II. Other= multifactorial III. Combination of these. ABOUBAKR ELNASHAR
  5. 5. 8/19/2020 9 I. ENDOMETRIAL FACTORS 1. Anatomic causes:  Polyp  Fibroid  Adhesion  Septum 2. Infection  Chronic endometritis  Vag/ut. Microbiome  Low abundance of endometrial Lactobacillus ABOUBAKR ELNASHAR 8/19/2020 10 3. Impaired function  Thin endometrium  Altered expression of adhesive molecules 4. Thrombophilia 5. Immunological factors ABOUBAKR ELNASHAR
  6. 6. 8/19/2020 11 II. GAMETE/EMBRYO FACTORS 1. Parental chromosomal anomalies 2. Poor-quality oocyte 3. Poor-quality spermatozoa 4. Zona hardening 5. Suboptimal culture conditions 6. Suboptimal embryo quality ABOUBAKR ELNASHAR 8/19/2020 12 III. OTHER= MULTIFACTORIAL 1. Suboptimal ovarian stimulation 2. Suboptimal ET 3. Hydrosalpinges 4. Endocrine 5. Endometriosis ABOUBAKR ELNASHAR
  7. 7. 8/19/2020 13 ABOUBAKR ELNASHAR 8/19/2020 14 INVESTIGATIONS I. ENDOMETRIAL  Anatomical  Immunological Disorders & Thrombophilia II. GAMETE/EMBRYO  Sperm Quality Tests  Oocyte Tests  Parental Karyotype III. OTHER  Adnexal Factors  Endocrine Investigations ABOUBAKR ELNASHAR
  8. 8. 8/19/2020 15 I. ENDOMETRIAL 1. Anatomical: 1. An evaluation of the pelvic anatomy for detection of Mullerian abnormalities using 3D US. Good Practice Point 2. No evidence to support the use of hysteroscopy in the absence of suspected uterine pathology in first cycle of IVF. Grade A evidence ABOUBAKR ELNASHAR 8/19/2020 16 3. ERA test with individualised ET time is not recommended. Grade B evidence ABOUBAKR ELNASHAR
  9. 9. 8/19/2020 17 2. Testing For infection Disorders:  Insufficient evidence to recommend Microbiome testing Grade D evidence  If infection such as tuberculosis is diagnosed, a course of antibiotics would be recommended as per NICE guidelines. Good practice point ABOUBAKR ELNASHAR 8/19/2020 18 3. Testing For Immunological Disorders:  Insufficient evidence to recommend  uNK or pNK cell testing Grade B, C evidence  endometrial& peripheral blood cytokine testing Grade C evidence  HLA incompatibility testing. Grade C evidence ABOUBAKR ELNASHAR
  10. 10. 8/19/2020 19 4. Testing for thrombophylia  Current evidence does not support testing for congenital thrombophilia  Further research is needed to establish whether or not APLA testing is indicated. Grade C evidence ABOUBAKR ELNASHAR 8/19/2020 20 II. GAMETE/EMBRYO 1 Sperm Quality Tests  There is insufficient evidence to support  Sperm aneuploidy testing  Epigenetic testing or  CASA for Sperm motility characteristics. Grade C evidence  Sperm DNA fragmentation testing. Grade C evidence ABOUBAKR ELNASHAR
  11. 11. 8/19/2020 21 2. Oocyte Tests:  AMH  weak predictor for clinical pregnancy.  Normal & good response to previous COS  favourable prognostic indicators for women with RIF planning on further IVF treatment. Grade C evidence ABOUBAKR ELNASHAR 8/19/2020 22 3. Parental Karyotype:  No evidence to support parental karyotype testing.  Some evidence that parental karyotype testing ±appropriate in the presence of additional risk factors such as:  Personal or family history of RM or  Higher-order RIF(≥6 consecutive failed ET) with no previous live-births Grade C evidence& Good practice point ABOUBAKR ELNASHAR
  12. 12. 8/19/2020 23 III. OTHER 1. An evaluation of the pelvic anatomy for detection of hydrosalpinges using TV US. Good Practice Point ABOUBAKR ELNASHAR 8/19/2020 24 2. Endocrine Investigations:  TSH testing can be offered. Grade B evidence  Vit D should be assessed in high risk groups, with treatment provided if deficiency is identified. Good practice point.  Insufficient evidence to recommend  Thyroid autoimmunity testing. Grade C evidence  Prolactin  Free androgen index. Grade C evidence  Diabetic screening for men or women Grade C evidence ABOUBAKR ELNASHAR
  13. 13. 8/19/2020 25 TREATMENT I. ENDOMETRIAL 1. Anatomical 2. Treatment for immunological dysfunction II. GAMETE/EMBRYO 1. Sperm 2. Genetic Counselling 3. Embryo quality and selection III. OTHERS 1. Lifestyle Changes 2. Ovarian stimulation strategies 3. Strategies to improve Embryo Transfer Technique 4. adnexal factors 5. endocrine conditions 6. Empirical treatment: ABOUBAKR ELNASHAR 8/19/2020 26 I. EDOMETRIAL 1. Anatomical causes  Endometrial polyps& submucosal fibroids should be removed. Grade A evidence  Insufficient evidence to support the removal of fibroids not distorting uterine cavity. Grade B evidence  An individualised approach to myomectomy after careful counselling for large intramural fibroids not distorting endometrial cavity. Good practice point ABOUBAKR ELNASHAR
  14. 14. 8/19/2020 27  Insufficient evidence to recommend hysteroscopic septal resection. Grade B evidence ABOUBAKR ELNASHAR 8/19/2020 28 2. Improving endometrial function  Insufficient evidence to recommend  Endometrial scratch. Grade B evidence  LMWH Grade B evidence  G-CSF  PRP  Sildenafil Grade C evidence ABOUBAKR ELNASHAR
  15. 15. 8/19/2020 29 3. Treatment for immunological dysfunction  IVIg is not recommended. Grade C evidence  Insufficient evidence to support the use of Steroid for women with a history of RIF, even in the presence of high pNK or high uNK cell levels. Grade C evidence ABOUBAKR ELNASHAR 8/19/2020 30 II. GAMETE 1. Sperm  No specific oral antioxidants recommended for the male partner.  Further study is required to identify individual antioxidant supplements that could improve sperm quality, implantation & LBR. Grade C evidence  No evidence to support the hyaluronic acid binding sperm selection technique for improving outcome Grade D evidence ABOUBAKR ELNASHAR
  16. 16. 8/19/2020 31  Insufficient data to support Intracytoplasmic morphologically selected sperm injection (IMSI). Grade B evidence  Surgical sperm retrival (SSR) should not be recommended unless indicated by azoospermia. Grade D evidence ABOUBAKR ELNASHAR 8/19/2020 32 2. Embryo quality& selection  There is some evidence to support blastocyst transfer. Grade B evidence  Assisted hatching  May improve CPR with RIF but in the absence of data on LBR  In combination with an association with multiple pregnancies, assisted hatching is not recommended. Grade B evidence ABOUBAKR ELNASHAR
  17. 17. 8/19/2020 33  Insufficient evidence to support the use of  TLI technology for embryo selection. Grade D evidence  PGT-A . Grade C evidence ABOUBAKR ELNASHAR 8/19/2020 34 3. Gamete Donation & Surrogacy  Insufficient evidence to recommend the use of donor gametes or surrogacy in unexplained RIF. Grade B evidence ABOUBAKR ELNASHAR
  18. 18. 8/19/2020 35 4. Counselling including genetic counselling:  {Failed IVF cycles can be associated with both short-term& long-term adverse psychological sequelae}. Grade B evidence  Counselling should be made available to all couples who have had a failed IVF cycle. Good practice point ABOUBAKR ELNASHAR 8/19/2020 36 III. OTHER 1. Lifestyle Changes  Men& women undergoing IVF should be advised  stop smoking  optimise their weight. Good practice point.  Women undergoing fertility treatment should be advised to take 400 IU of supplemental vit D daily. ABOUBAKR ELNASHAR
  19. 19. 8/19/2020 37 2.Strategies to improve Embryo Transfer Technique  Good quality evidence for all ET to be performed under ultrasound guidance. Grade A evidence  Insufficient evidence identifying the ideal intrauterine location for transferring an embryo  Most studies agree that catheter tip should be >15 mm from the fundus  No data specific to women with RIF. Grade C evidence ABOUBAKR ELNASHAR 8/19/2020 38  Good quality evidence for a full bladder at ET, in order to achieve ‘passive’ straightening of the uterocervical angle  Insufficient evidence for or against use of tenaculum. Grade C evidence  Insufficient evidence to recommend cervical dilatation in settings of previous ‘difficult’ ET.  If performed, it should be in the cycle prior to ET& not on the day of ET.  There is no evidence that relates specifically to management of RIF. Grade. C evidenceABOUBAKR ELNASHAR
  20. 20. 8/19/2020 39  Bed rest  Good quality evidence that bed rest after ET does not significantly affect LBR  Some evidence that bed rest may be detrimental to embryo implantation rates. Grade B evidence  Insufficient evidence to recommend the use of  Fibrin sealants or  Antibiotics after ET.  There is no evidence that relates specifically to management of RIF. Grade C evidence ABOUBAKR ELNASHAR 8/19/2020 40  Evidence for the use of hyaluronan-enriched culture media to improve LBR in unselected populations  No clear evidence specifically for women with RIF. Grade B evidence  Insufficient evidence to recommend routine elective FET for women with RIF. Grade D evidence  Additional data on multiple pregnancy rates are required to understand the role of sequential ET for women with RIF. Grade B evidence ABOUBAKR ELNASHAR
  21. 21. 8/19/2020 41 3. Ovarian stimulation strategies  No evidence to indicate recommendation of a specific strategy for COS. Grade B evidence ABOUBAKR ELNASHAR 8/19/2020 42 4. Laparoscopic salpingectomy recommended for women undergoing IVF with a history of RIF& ultrasound-visible hydrosalpinges. Grade A evidence ABOUBAKR ELNASHAR
  22. 22. 8/19/2020 43 5.Optimise endocrine conditions  Some evidence for women who are already receiving thyroxine for subclinical hypothyroidism  Dose should be titrated for a preconceptual TSH level 0.4 - 2.5 mU/L Grade B evidence  Euthyroid women with thyroid autoimmunity should not be provided thyroxine. Grade C evidence  Insufficient evidence to recommend treatment for hyperprolactinemia for women with a history of RIF solely to improve pregnancy outcome. Grade B evidence ABOUBAKR ELNASHAR 8/19/2020 44 CONCLUSIONS ABOUBAKR ELNASHAR
  23. 23. 8/19/2020 45 INVESTIGATIONS I. ENDOMETRIAL 1. Anatomical: 1. 3 DUS: Green 2. Screening hysteroscopy: Red 3. ERA: Red 2. Immunological 1. uNK cells: Amber 2. pNK cells: Red 3. uCytokines: Red 4. pCytokines: Red 5. Genital micobiome: Red 6. HLA incompatability: Red 3. Thombophilia: 1. APA: Amber 2. Congenital thrombophilia: Red ABOUBAKR ELNASHAR 8/19/2020 46 II. GAMETE/EMBRYO 1. Sperm: 1. Sperm aneuplody: Amber 2. DNF: Amber 3. Sperm epigenetis: Red 4. CASA: Red 2. Oocyte: AMH: Amber 3. Genetic testing: Karyotype: Red Amber: High order RIF or additionalABOUBAKR ELNASHAR
  24. 24. 8/19/2020 47 III. OTHER 1. Hydrosalpinx: US: Green 2. Endocrine: 1. TSH: Green 2. Tab: Amber 3. PRL: Red 4. FAI: Red 5. HbA1c: Red ABOUBAKR ELNASHAR 8/19/2020 48 TREATMENT I. Endometrial 1. Anatomical 1. Polymectomy: Green 2. Myomectomy of Submucous F: Green 3. Septoplasty: Amber 4. Improve endometrial function: 1.Heparin: Red 2.Sildenafil: Red 3.GCSF: Red 4.PRP: Red ABOUBAKR ELNASHAR
  25. 25. 8/19/2020 49 3. Immunological: 1. Endometrial scratching: Amber 2. Corticosteroids: Amber 3. IVIg: Red ABOUBAKR ELNASHAR 8/19/2020 50 II. GAMETE/ Embryo 1. Counseling including genetic counseling: Green 2. Sperm: 1. Antioxidants: Red 2. Hyaluronic ac binding for sperm selection: Red 3. IMSI: Red 4. Surgical sperm retrival in absence of azospermia: Red 3. Embryo: 1. Blastocyst transfer: Amber 2. Assissted H: Red 3. TL imaging: Red 4. PGT-A: Red 4. Donor gametes/Surrogacy: Red ABOUBAKR ELNASHAR
  26. 26. 8/19/2020 51 III. OTHER 1. Life style: 1. Smoking cessation: Green 2. Optimizing wt: Green 3. Vit D supplementation: Green 2. Ovarian stimulation particular protocol: Amber ABOUBAKR ELNASHAR 8/19/2020 52 3. Embryo transfer: 1. US guided: Green 2. Full bladder: Green 3. Catheter tip >15mm from fundus: Amber 4. Cervical dilatation: Amber 5. Hyaluronic ac ET medium: Amber 6. Cervical mucous removal: Red 7. Bed Rest: Red 8. Fibrin sealant: Red 9. Antibiotics: Red 10. FET: Red 11. Sequential ET: Red ABOUBAKR ELNASHAR
  27. 27. 8/19/2020 53 4. Endocrine: 1.Treatment of Subclinical hypothyroidism: Green 2.Treatment of hyperprolactinaemia when indicated: Green 5. Hydrosaplinx: salpingectomy: Green ABOUBAKR ELNASHAR

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